Beruflich Dokumente
Kultur Dokumente
1
Department of Endocrinology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine,
Xiangyang, Hubei 441000, P.R. China; 2Orient Health Care, StegoTech LLC, King of Prussia, PA 19406, USA
DOI: 10.3892/etm.2017.4459
or ethical approval was required for the study. The design reporting; and ) incomplete outcome data, and other sources
and implementation of this study conformed to the criteria of bias.
of Preferred Reporting Items for Systematic Reviews and The assessment of the quality of the research was conducted
Meta-Analyses (PRISMA) (9). using the GRADE form (11). Evidence was divided into the
following levels: high quality (our confidence in the estimated
Eligibility criteria. Research that met the requirements below effect will unlikely be changed by further research), moderate
was included in the study: ) the study design of the reviewed quality (our confidence in the estimated effect is likely to be
research is a randomized controlled trial (RCT); ) patients: changed by further research), low quality (our confidence in
TIA/minor stroke patients aged 18; ) interventions: the trial the estimated effect is very likely to be changed by further
group received Clop + ASA, while the control group received research), very low quality of the evidence (we remain quite
ASA alone; and iv) outcomes: incidence of recurrent stroke, uncertain about the estimated effect).
vascular mortalities, myocardial infarction (MI), and major
hemorrhagic events. Statistical analysis. The relative risk was estimated with a
Exclusion criteria for the study were: ) unpublished 95% confidence interval for binary outcomes. I2 was used
studies; ) studies without assessment of the measurement in tests for homogeneity. I2 above 50% suggested significant
indexes; ) studies with missing data for which statistical heterogeneity and that the random effects model was expected
analysis cannot be performed; and ) repeatedly published to be employed, and if not the fixed effect model was to be
studies or general reviews. employed (12). When significant heterogeneity was present,
sensitivity analysis was used to identify potential sources
Search strategy. Databases listed as below were searched of heterogeneity. If a study was included and the total RR
independently by two researchers J.T. and M.Z.Z. (PubMed, changed substantially, this suggested that the study had a
Cochrane, EMBase, Medline, and Web of Science) to large bias and the result should be interpreted carefully.
confirm eligible studies. The following keywords were used: Based on the sample size, cumulative meta-analysis was used
aspirin, antiplatelet therapy, cerebral ischemia, clopidogrel, to evaluate the influence of citing studies with large sample
minor stroke, randomized controlled trial and transient size on the incorporated result. The Egger's test and Egger's
ischemic attack. The screening study was conducted on the funnel plot were performed for assessing any publication bias
screened full-text in order to evaluate additional possible in the studies included (13). Results were assumed statistically
eligible trials. significant when P<0.05. RevMan 5.2 and R 3.1.1 were used to
The studies were independently screened and verified in perform the statistical analyses.
accordance with the inclusion as well as exclusion criteria.
Titles and abstracts were first reviewed to exclude studies that Results
did not comply with the inclusion criteria. For the studies that
were potentially eligible, a second screening was conducted Selection of studies and their characteristics. The retrieval and
by reading the whole text. Any disagreement was solved by a screening results of this study are shown in Fig. 1. A total of
third reviewer (CKH) through consultation. 168 relevant potential studies were obtained through a prelimi-
nary screening, while 131 studies were excluded by reading of
Data extraction and measurement of outcome. A piloted their titles and abstracts. The full contents of the remaining
extraction datasheet was employed with the following infor- 37 studies were reviewed, with 32 of them eliminated (27 did
mation covered: research title, number of patients, average not conform to the criteria, 3 were systematic reviews, and
age of patients, percentage of male patients, received drug 2 were absent of data). Five RCT studies conforming to the
dose of the trial group, received drug dose of the control criteria were selected for the meta-analysis.
group, time interval from onset of symptoms to entering Main characteristics of the 5 RCT studies used for the
studies, treatment duration, and percentage of patients lost meta-analysis are shown in Table I. The studies were published
to follow-up. from 2005 to 2014; 3 were carried out in Canada, 1 in China,
The investigators extracted all data from the reports. Any and 1 in the UK. The sample sizes ranged from 107 to 5,170
disagreement was settled through consultation. When neces- (the total sample size was 9,527 cases). The average age of
sary, we contacted the corresponding authors by e-mail to gain patients in these 5 RCT studies was 62-68 years, with a male
accurate data. The primary outcome encompassed recurrent predominance (53-69%). The duration from onset of symptoms
stroke, and MI and vascular mortalities were the secondary to inclusion into studies (start of treatment) ranged from 24 h to
outcomes, and major hemorrhagic events were for the safety 3 months (three articles in 72 h; two articles within 3 months).
outcome. The treatment durations ranged from 7 days to 3.5 years (three
articles in 3 months; two articles in 3.5 years).
Evaluation of risk of bias and the assessment of the quality
of included research. With reference to version 5.1.0 of the Risk of bias and evidence level. The risks of bias of the five
Cochrane Handbook for Systematic Reviews of Interventions, aforementioned RCT studies are shown in Fig. 2. Randomized
risk of bias was assessed for this study (10). After reviewing sequence generation was unclear in ASA failure and
all included articles, a level of unclear, low or high was Clop + ASA for reduction of emboli in symptomatic carotid
assigned to the following areas: ) random sequence genera- stenosis because these studies only described randomization
tion; ) blinding of personnel and participants; ) allocation instead of the process of random sequence generation. The
concealment; ) blinding of outcome assessment; ) selective remaining studies were assumed to have low risk of bias.
326 EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 324-332, 2017
CHANCE 5,170 62 66 Asp (76-300 mg load Asp (76-300 mg 72 h 90 days 0.7 (14)
then 75 mg od first 12 days) load then 75 mg od)
+ Clop (300 mg load
then 75 mg od)
PASTER 392 68 53 Asp (81 mg od) Asp (81 mg od) 24 h 90 days 1.79 (15)
+ Clop (300 mg load
then 75 mg od)
CARESS 197 65 69 Asp (75 mg load) Asp (75 mg od) 72 h 7 days None (16)
+ Clop (300 mg load
then 75 mg od)
Failure 888 66 65 Asp (325 mg od) Asp (325 mg od) 150 days 3.5 years NR (17)
+ Clop (75 mg od)
SPS3 3,020 63 65 Asp (325 mg od) Asp (325 mg od) 150 days 3.5 years NR (18)
+ Clop (75 mg od)
Figure 1. Flow chart of literature retrieval and screening. Figure 2. Cochrance chart of risk of bias assessment.
ZHOU et al: SYSTEMATIC REVIEW AND META-ANALYSIS OF CLOP + ASA FOR MINOR STROKE OR TIA 327
Table II. Clop + ASA compared with ASA for TIA/minor stroke patients.
Moderate
38/1,000 41/1,000
(32-54)
Stroke recurrence Study population
110/1,000 84/1,000 RR=0.76 9,328 ++++
(74-96) (0.67-0.87) (5 studies) High
Moderate
117/1,000 89/1,000
(78-102)
Major hemorrhage Study population
2/1,000 3/1,000 RR=1.55 9,527 +++-
(2-7) (0.72-3.36) (5 studies) Moderate
Moderate
2/1,000 3/1,000
(1-7)
Clop, clopidogrel; ASA, aspirin; TIA, transient ischemic attack; MI, myocardial infarction.
GRADE was employed to evaluate the quality of evidence significant (P<0.0001). This analysis indicated that studies with
and recommended level (Table II). The results showed that small sample sizes may overestimate the effect of Clop + ASA
recurrent strokes, MIs, and vascular mortalities were high in lowering recurrent stroke.
quality evidence, while major hemorrhagic events were
moderate quality. Secondary outcome: myocardial infarction and vascular
mortality. The incidence of MI and vascular mortalities
Major outcome: recurrent stroke. The incidence of recurrent was 2.33% in the Clop + ASA group and 2.13% in the ASA
stroke in the group of Clop + ASA was 8.38%, while the group. Compared with ASA, the incidence of MI as well
incidence in the ASA group was 10.99%. Compared with as vascular mortalities was not significantly increased in
ASA, Clop + ASA resulted in a significantly lower incidence of the group with Clop + ASA (RR=1.08, 95% CI=0.83-1.41,
recurrent stroke of the group with TIA/minor stroke (RR=0.76, P=0.56, Fig. 5A). No heterogeneity was present between the
95% CI=0.67-0.87, P<0.0001, Fig. 3A). No heterogeneity was trial and control groups (I2=0%). Egger's regression line
present between the trial and control groups (I2=19%). Egger's (Fig. 5B) was constructed and did not show evidence of any
regression line (Fig. 3B) was made, and a null hypothesis was publication bias with the use of Egger's test (P-value for bias
tested whether the regression line intercepted 0 or not. No bias was 0.887).
was suggested with the use of Egger's test (P for bias turned Cumulative meta-analysis was performed based on
out 0.72). sample sizes (Fig. 6). The total RR was initially unstable as
Cumulative meta-analysis was performed based on it fluctuated between values of >1.0 and <1.0. However, after
sample sizes (Fig. 4). The treatment effect was initially large, accumulating additional studies, the total RR became stable
although after adding studies with large sample sizes, the and the confidence interval became narrow. This analysis
confidence interval narrowed, and the treatment effect became suggested that combination therapy does not increase the
smaller and stable, albeit the treatment effect was still highly incidence of vascular mortalities.
328 EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 324-332, 2017
Figure 3. Meta-analysis of recurrent stroke for Clop + ASA compared with ASA. (A) Forest plot of recurrent stroke in two groups; (B) Egger's regression line
of recurrent stroke for Clop + ASA compared with ASA. Clop, clopidogrel; ASA, aspirin.
Figure 4. Accumulative meta-analysis of recurrent stroke for Clop + ASA compared with ASA. Clop, clopidogrel; ASA, aspirin.
Safety outcome. The incidence of major hemorrhagic and the Egger's test did not suggest any publication bias
events was 0.33% in the Clop + ASA group and 0.21% (P-value for bias was 0.9723).
in the ASA group. Compared with ASA, the incidence Cumulative meta-analysis was performed based on
of hemorrhagic events was not increased in the group of sample sizes (Fig. 8). The treatment effect was large at the
Clop + ASA (RR=1.55, 95% CI=0.72-3.36, P=0.26, Fig. 7A). beginning, although after adding studies with large sample
No heterogeneity was present between the trial and control sizes, the confidence interval narrowed, and the treatment
groups (I2=0%). Egger's regression line (Fig. 7B) was plotted effect became smaller and stable. This analysis suggested that
ZHOU et al: SYSTEMATIC REVIEW AND META-ANALYSIS OF CLOP + ASA FOR MINOR STROKE OR TIA 329
Figure 5. Meta-analysis of the incidence of MI and vascular mortalities for Clop + ASA compared with ASA. (A) Forest plot of the incidence of MI and
vascular mortalities in two groups; (B) Egger's regression line of MI and vascular mortality for Clop + ASA compared with ASA. MI, myocardial infarction;
Clop, clopidogrel; ASA, aspirin.
Figure 6. Accumulative meta-analysis of the incidence of MI and vascular mortalities for Clop + ASA compared with ASA. MI, myocardial infarction; Clop,
clopidogrel; ASA, aspirin.
combination therapy does not increase the incidence of major recurrent stroke and vascular events along with total mortalities,
hemorrhagic events. without increasing the risk of hemorrhage when compared
with mono-antiplatelet therapy for stroke/TIA patients (19).
Discussion However, another meta-analysis showed the opposite result,
namely patients with vascular disease taking Clop + ASA
Of two relevant meta-analyses published in 2012, one showed may experience an increased risk of fatal hemorrhage (20).
that dual antiplatelet therapy may lower the incidence of Therefore, the effects of the two antiplatelet drugs when used in
330 EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 324-332, 2017
Figure 7. Meta-analysis of the incidence of major hemorrhagic events for Clop + ASA compared with ASA. (A) Forest plot of the incidence of major hemor-
rhagic events in two groups. (B) Egger's regression line of major hemorrhagic events for Clop + ASA compared with ASA. Clop, clopidogrel; ASA, aspirin.
Figure 8. Accumulative meta-analysis of the incidence of major hemorrhagic events for Clop + ASA compared with ASA. Clop, clopidogrel; ASA, aspirin.
combination require further study. Since a significant amount is not significantly changed by such treatment (RR=1.08,
of research results have been reported in recent years, we 95% CI=0.83-1.41, P=0.56). These findings are inconsistent
evaluated the safety and efficacy of treatment with Clop + ASA with the results of previous meta-analyses (19,20). Transcranial
compared with ASA alone for TIA/minor stroke patients. Doppler ultrasound recordings provided supportive evidence
The primary and secondary outcomes of this study show in these studies as the number of microembolic signals is
that the incidence of recurrent stroke can be significantly proportional to recurrent stroke and risk of other vascular
decreased with the treatment of Clop + ASA (RR=0.76, events. Both CARESS (16) and Clop + ASA for infarction
95% CI=0.67-0.87, P<0.0001), and MI and vascular mortalities reduction (CLAIR) (21) demonstrate that compared with
ZHOU et al: SYSTEMATIC REVIEW AND META-ANALYSIS OF CLOP + ASA FOR MINOR STROKE OR TIA 331
ASA alone, combination therapy of Clop + ASA significantly Research Project of Hubei Provincial Department of Education
reduces microembolic signals. Therefore, the risks of recurrent in 2014 (B2014051).
stroke as well as other vascular events are reduced with
combination therapy as well. References
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